Estrogen replacement therapy in elderly women has been reported to diminish the risk of developing Alzheimer's disease (AD) and to improve response to anti-cholinesterase therapy in women already diagnosed with AD. Further, recent evidence indicates that estrogen may modulate the expression of neuronal growth factors and their receptors in the brain. These findings suggest that neuronal plasticity in the brain may be modulated in part by estrogen-linked mechanisms. To investigate this possibility, our laboratory has explored interactions of estrogen-responsive neurons with growth factors and their receptors. We have found extensive co-expression of estrogen and neurotrophin systems in both cortical regions and forebrain projections to cortical regions in the brains of rodents and primates. Studies in this proposal will examine the effects of neuronal injury and estrogen loss on neural plasticity to test the hypothesis that estrogens modulate neural plasticity to test the hypothesis that estrogens modulate neural plasticity through interactions with neurotrophic factor systems in the brain. Mechanisms of such interactions will be elucidated. This work will build upon techniques and methods that are will-established in the PI's lab and that have led to useful insights into the nature of neurotrophin biology in the rodent and primate brains. The specific aims will be addressed: Aim 1: Do neuronal populations in the primate and rodent brains co-express estrogen receptors and neurotrophins or their receptors, reflecting co- modulation of these systems? Aim 2: What effects do natural fluctuations in estrogen levels exert on cortical synapse density and on expression of NGF, BDNF and neurotrophin receptors in the brain? Aims 3 and 4: What effect does estrogen loss exert on synapse density in cortical target regions, and on expression of neurotrophins and their receptors, in the brains of adult and aged rats (Aim 3) and in the brains of adult primates (Aim 4)? Aim 5: Do estrogens and growth factors act synergistically to enhance neural plasticity? These studies will provide insights regarding estrogen effects on going, cognition, and neurotrophic factors, leading to potential novel therapeutic approaches to AD.